Reporter: J. Nicholas Lukens, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 5, 2010

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Presenter: V. Westeel, MD, on behalf of the Intergroupe Francophone de Cancerologie Thoracique

Background

This is an update of a previously reported French Phase III randomized trial (DePierre, JCO 2002) comparing neo-adjuvant chemotherapy followed by surgery to surgery alone for patients with resectable non-small cell lung cancer (NSCLC).

There had been several studies demonstrating a benefit to pre-operative chemotherapy in patients with Stage IIIA NSCLC (Roth, Lung Cancer,1998; Rosell, N Engl J Med, 1994); however, this area of research remains complex and controversial.

Overall survival (OS) rates for patients with T2N0 and Stage II disease remain relatively poor (5 year OS of 50% and <50%, respectively); this study included a broader patient population, including those with Stage I (except T1N0), II, and IIIA disease

The study initially demonstrated:

A delayed benefit of pre-operative chemotherapy on OS (8.6% benefit at 4 years), and

An interactionwith stage, with a positive effect of pre-operative chemotherapy on survival in StageI and II patients, but not Stage IIIA.

The objective of this update was to evaluate the survival beyond 10 years of this cohort of patients treated with pre-operative chemotherapy, and to asses the durability of the survival benefit seen.

Methods

Patients randomized to pre-operative chemotherapy (PCT) consisting of 2 cycles of Mitomycin, Ifosfamide, and Cisplatin, followed by surgery, and an additional 2 cycles post-operatively for objective responders, versus surgery alone.

In both arms, patients with pT3 or pN2 disease, or incomplete surgery, received adjuvant thoracic radiotherapy (up to 60 Gy).

Primary endpoint: Overall Survival (OS), powered for a difference in OS of 15% at 2 years

Follow-up: CT Chest and fiberoptic bronchoscopy every 6 months for first 2 years, then annually until 7 years, then annual follow-up with procedures at the discretion of the investigator beyond 7 years.

Results

355 patients were randomized as part of this study (179 in PCT arm versus 176 in surgery arm)

Median follow-up was 13.8 years

Comparing the 2 groups, there were more N2+ patients in the PCT arm compared to the surgery arm (42% versus 28%, respectively, p=0.065)

Compliance with follow-up CT Chest fell to 22% after 5 years

The 8% overall survival benefit with PCT at 5 years was maintained at 10 years, although this did not reach statistical significance (10 year OS 29.4% for PCT versus 20.8% for surgery, P=0.12)

Adjusting for age, T and N stage in multivariate analysis, neo-adjuvant chemotherapy led to a significant improvement in OS (HR 0.69, P=0.0055)

OS was significantly improved with PCT in patients who underwent lobectomy (p = 0.04), but not in those who underwent pneumonectomy.

The 10-year recurrence-free survival rate was 38.2% in the S arm, versus 54.6% in the PCT arm (p = 0.001).

Interestingly, there was a lower rate of bone metastases in the patients treated with neo-adjuvant chemotherapy compared to surgery alone (5% vs. 13%, p=0.004), but there was no difference in the rate of brain metastases.

At exploratory subgroup analyses:

The 10-year OS rate for patients with Stage I and II disease was 23.1% in the surgery arm, vs. 37.6% in the PCT arm (p = 0.04).

The survival difference between the two arms for patients with stage IIIA disease was not significant.

The rate of non-cancer deaths was identical in the two arms.

The mortality rate from second malignant neoplasms was also similar (6.9% in the S arm and 5% in the PCT arm).

Author’s Conclusions

However, an 8% survival benefit in favor of neo-adjuvant chemotherapy remained stable beyond 10 years, and the multivariate analysis suggested a long-term benefit of neoadjuvant chemotherapy.

Clinical Implications

This study has several limitations which limit its applicability in current clinical practice:

The treatment arms were not balanced, with more patients in the pre-operative chemotherapy arm having N2+ disease

The chemotherapy regimen used in the trial is not standard in the United States, and is a combination of neo-adjuvant and adjuvant chemotherapy; furthermore, it is unclear how many patients in the PCT arm received all 4 planned cycles of chemotherapy.

Nevertheless, the trial is suggestive of a benefit to neo-adjuvant chemotherapy in early stage NSCLC, especially when considered in light of another recently published Phase III study:

Pisters et al., (JCO 2010, SWOG 9900): Phase III trial of induction Carbo/Taxol in early stage NSCLC: This trial demonstrated a trend towards improved overall survival with use of neoadjuvant chemotherapy, but the trial was closed early after a benefit to adjuvant chemotherapy was reported in other studies.

When taken together, these studies suggest that there may be an overall survival benefit to pre-operative chemotherapy in early stage (Stage IB to IIIA) NSCLC that did not reach significance due to lack of power.

The finding on subgroup analysis of a survival benefit in T2N0 and Stage II patients, but not in Stage IIIA patients, is difficult to reconcile with other (smaller) Phase III data demonstrating a survival advantage in Stage IIIA patients;

This calls into question the dictum that pre-operative chemotherapy should be reserved for Stage IIIA patients

Additional studies would be needed to clarify the role of neo-adjuvant chemotherapy in Stage IIIA disease

Therefore, it remains to be determined whether pre-operative or adjuvant chemotherapy represents the optimal approach in this subset of patients, and further research is warranted.

In summary, this is an intriguing study that is a valuable contribution to the literature. It raises many questions that do not have ready answers, and which will hopefully be addressed in future trials.